The present invention relates to novel piperidine, tetrahydropyridine and piperazine derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use thereof for the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake. The compounds of the invention also possess antagonistic activity at 5-HT1A receptors and are considered to be particularly useful for the treatment of depression.
Selective serotonin (or 5-HT) reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step forward in the treatment of depression because they have fewer and less severe side effects compared to first generation antidepressant (tricyclics and non-selective MAO inhibitors). The side effects associated with first generation antidepressants are such that they cause some patients to withdraw from treatment.
SSRIs and all other antidepressants currently available suffer from a serious drawback in that several weeks of treatment are necessary to produce the therapeutic effect. The late onset of action is a significant problem, particularly in the treatment of patients with severe depression and suicide potential. Further, one in three patients are not responsive to SSRIs.
Electrophysiological experiments in rats have shown that acute administration of SSRIs reduces firing of 5-HT neurons of dorsal raphe nucleus in the rodent brain, whereas sustained treatment with SSRIs leads to normalization of the firing activity of the 5-HT neurons (Arborelius, L. et al. Naunyn-Schmiedeberg""s Arch. Pharmacol. 1995, 352, 157; Gartside, S. E. et al. Br. J. Pharmacol. 1995, 115, 1064: Chaput, Y. et al. Naunyn-Schmiedeberg""s Arch. Pharmacol. 1986, 33, 342).
Further, it has been shown that the recovery of the firing activity of 5-HT neurons is linked to desensitization of somatodendritic 5-HT1A autoreceptors (Le Poul, E. et al, Naunyn-Schmiedeberg""s Arch. Pharmacol. 1995, 352, 141; Invernizzi, R. et al, Eur. J. Pharmacol. 1994, 260, 243).
It has thus been suggested that simultaneous administration of SSRIs and an agent causing rapid desensitization or inhibition of the 5-HT1A receptor mediated feed back mechanism would lead to rapid onset of antidepressive effect (Artigas, F. et al, Trends Neurosci. 1996, 19, 378; De Vry, J., et al, Drug News Perspec. 1996, 9, 270).
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists inhibit the decrease in firing caused by acute administration of serotonin reuptake inhibitors.
Further, treatment with a combination of pindolol (a well known 5-HT1A receptor and xcex2-adrenoceptor antagonist) and SSRIs has been evaluated in clinical trials. A remarkable improvement of the mood of patients was reported within one week. In addition, combined administration of pindolol and an SSRI was shown to have a good effect on patients who were non-responsive to treatment with currently available antidepressants (Artigas F. et al., Arch. Gen. Psychiatry, 1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995, 15, p 217-222).
Several patent applications have been filed which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).
In EP-A1-529 462, certain 1,4-benzodioxan derivatives having the general formula 
wherein B is an optionally substituted indol-3-yl group and Q is CnH2n wherein n is 1, 2, 3, 4, 5, or 6 are disclosed. These compounds are said to have serotonin agonistic and serotonin antagonistic activity as well as serotonin reuptake inhibiting activity and to be useful as anxiolytics, antidepressants, antipsychotics, antihypertensives, and cerebroprotective agents.
In U.S. Pat. No. 5,002,948, Perregaard et al. disclose related indoles, indazoles, 2-indolones and 2,3-dihydro derivatives thereof having the formula 
wherein X is xe2x80x94CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94COxe2x80x94; and Ar is 
wherein Y is O, or S, Z is O, S, or xe2x80x94CH2xe2x80x94, and n is 1, 2, or 3.
These compounds are valuable 5-HT1A receptor ligands.
It is the object of the present invention to provide compounds with potent serotonin reuptake inhibiting activity as well as antagonistic properties at 5-HT1A receptors. Such compounds may be useful as fast onset of action medicaments for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.
A further object of the present invention is to provide a pharmaceutical composition comprising the above compounds as active ingredients.
The invention then, inter alia, comprises the following alone or in combination:
A piperidine, tetrahydropyridine or piperazine derivative having the formula: 
any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein
B is C1-10-alkylene, C2-10-alkenylene or C2-10-alkynylene;
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CR4R5xe2x80x94; and
Y is xe2x80x94CR6R7xe2x80x94, xe2x80x94CR6R7xe2x80x94CR8R9xe2x80x94, or xe2x80x94CR6xe2x95x90CR7xe2x80x94; or
X and Y together form a group xe2x80x94CR4xe2x95x90CR5xe2x80x94, or xe2x80x94CR4xe2x95x90CR5xe2x80x94CR6R7xe2x80x94;
Z is xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94;
W is N, C, or CH, and the dotted line is an optional bond;
R4, R5, R6, R7, R8 and R9 are each independently selected from hydrogen, halogen, trifluoromethyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkoxy,
C1-6-alkylthio, amino, C1-6-alkylamino, C1-6-dialkylamino, phenylamino or phenyl-C1-6-alkylamino wherein the phenyl group may be substituted, acylamino, hydroxy, xe2x80x94SH, cyano, nitro, xe2x80x94COOR18, xe2x80x94SO2xe2x80x94R19 and
C1-6-alkyl substituted with a substituent selected from halogen, C1-6-alkoxy, C1-6-alkylthio, amino, C1-6-alkylamino, C1-6-dialkylamino, acylamino, hydroxy, xe2x80x94SH, cyano, nitro, xe2x80x94COOR18 and xe2x80x94SO2xe2x80x94R19;
R18 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, phenyl or phenyl-C1-6-alkyl wherein the phenyl groups may be substituted, amino, C1-6-alkylamino or C1-6-dialkylamino, and
R19 is C1-6-alkyl, amino, C1-6-alkylamino, C1-6-dialkylamino, phenyl or phenyl-C1-6-alkyl wherein the phenyl groups may be substituted;
A is a bicyclic ring selected from 
xe2x80x83wherein E1, E2 and E3 are selected from O, S, N, NR11, C, CR12 and CHR13, and the dotted line indicates an optional bond, provided that E2 and E1 and/or E3 may not simultaneously be O, or S;
R1, R2, R3, R12, R13, R14, R15, R16 and R17 are each independently selected from hydrogen, halogen, trifluoromethyl, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, hydroxy, formyl, acyl, amino, C1-6-alkylamino, C1-6-dialkylamino, acylamino,
C1-6-alkoxycarbonylamino, aminocarbonylamino, C1-6-alkylaminocarbonylamino, C1-6-dialkylaminocarbonylamino, nitro, cyano and xe2x80x94SO2xe2x80x94R19, wherein R19 is C1-6-alkyl, amino,
C1-6-alkylamino, C1-6-dialkylamino, phenyl, or phenyl-C1-6-alkyl wherein the phenyl groups may be substituted;
R11 is selected from hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl,
C3-7-cycloalkyl-C1-6-alkyl, phenyl or phenyl-C1-6-alkyl wherein the phenyl group may be substituted, acyl, formyl and xe2x80x94SO2xe2x80x94R19, wherein R19 is C1-6-alkyl, amino, C1-6-alkylamino, C1-6-dialkylamino, phenyl or phenyl-C1-6-alkyl wherein the phenyl groups may be substituted;
provided that at least one of R4-R9 is different from hydrogen when A is a group of formula (If) 
In one embodiment, the present invention relates to a compound wherein A is selected from the groups of formula (Ic), (Id) and (Ie) 
wherein E1, E2, E3, and R14, R15, R16 and R17 are as defined in claim 1 and E5 is N, C or CR12.
In a further embodiment, the present invention relates to a compound wherein the bicyclic ring A is selected from the groups (If) to (Iq): 
which is attached to the remainder of the compound of formula (I) via a carbon atom or a nitrogen atom in any of the two rings and
wherein the dotted line is an optional bond, E6 is O or S, and wherein any of the carbon atoms in the ring may be substituted with any of the substituents defined for R12-R17 above, and wherein the nitrogen atoms in the ring may be substituted with any of the substituents defined above for R11.
In a preferred embodiment, the present invention relates to a compound wherein A is a group of formula (Ih), (Ij) or (Iq).
In a more preferred embodiment, the present invention relates to a compound wherein A is a group of formula (Ih) wherein E6 is O. Such compound is preferably attached to the remainder of the derivative of formula (I) via position 3 in the five-membered ring.
In a further embodiment, the present invention relates to a compound wherein A is a group of formula (If).
In a final embodiment, the present invention relates to a compound wherein
B is C1-6-alkylene, C2-6-alkenylene, or C2-6-alkynylene;
X is xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; and
Y is xe2x80x94CR6R7xe2x80x94, xe2x80x94CR6R7xe2x80x94CR8R9xe2x80x94, or xe2x80x94CR6xe2x95x90CR7xe2x80x94; and
Z is xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94;
W is N, C, or CH;
R6, R7, R8 and R9 are each independently selected from hydrogen, halogen, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, amino, C1-6-alkylamino, C1-6-dialkylamino, phenylamino or phenyl-C1-6-alkylamino wherein the phenyl group may be substituted, hydroxy, cyano, nitro, xe2x80x94COOR18, xe2x80x94SO2xe2x80x94R19 and
C1-6-alkyl substituted with halogen, C1-6-alkoxy, C1-6-alkylthio, amino, C1-6-alkylamino,
C1-6-dialkylamino, acylamino, hydroxy, cyano, nitro, xe2x80x94COOR18 or xe2x80x94SO2xe2x80x94R19;
R18 is hydrogen, C1-6-alkyl, amino, C1-6-alkylamino or C1-6-dialkylamino;
R19 is C1-6-alkyl, amino, C1-6-alkylamino or C1-6-dialkylamino;
R1, R2, R3, R12, R13, R14, R15, R16 and R17 are each independently selected from hydrogen, halogen, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, hydroxy, amino, C1-6-alkylamino, C1-6-dialkylamino, nitro and cyano; and
R11 is selected from hydrogen, C1-6-alkyl, phenyl or phenyl-C1-6-alkyl wherein the phenyl group may be substituted, acyl, formyl and xe2x80x94SO2xe2x80x94R19, wherein R19 is C1-6-alkyl, amino, C1-6-alkylamino or C1-6-dialkylamino.
Specific compounds of the invention are compounds selected from
1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-butene-4-yl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,
1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,
1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,
4-[Benzofuran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)-1-proyl]piperazine,
1-[8-Cyano-1,4-benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)propyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine
1-[1,4-Benzodioxan-5-yl]-4-[2-(6-bromobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(4-chlorobenzofuran-3-yl)-1-propyl]piperazine
1-[1,4-Benzodioxan-5-yl]-4-[4-(4-methylbenzofuran-3-yl)-1-butyl]piperazine
1-[1,4-Benzodioxan-5-yl]-4-[4-(4-chlorobenzofuran-3-yl)-1-butyl]piperazine
1-[1,4-Benzodioxan-5-yl]-4-[4-(7-chlorobenzofuran-3-yl)-1-butyl]piperazine
4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,
4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]piperidine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperazine,
1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperazine,
1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,
1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,
4-[6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,
1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,
1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperidine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperidine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperadine,
4-[2-(6-Chloro-1H-indol-3-yl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperadine,
1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperadine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperidine,
1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,
1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperadine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperidine,
1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperazine,
1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,
1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,
1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]tetrahydropyridine,
1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,
1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,
4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperdine,
1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,
1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.
Particularly preferred compounds are
1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,
1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,
1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine,
1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine, and 4-[Benzofuran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,
or a pharmaceutically acceptable acid addition salt thereof.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent
In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors.
In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.
In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
In particular, the invention relates to a method for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a living animal body, including a human, in need thereof.
Due to their combined antagonism of 5-HT1A receptors and serotonin reuptake inhibiting effect, the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
The compounds claimed herein are considered particularly useful for the treatment of depression requiring fast onset of antidepressive effect, or a depression which is resistant to other antidepressants.
Halogen means fluoro, chloro, bromo, or iodo.
C1-6-alkyl means a straight or branched chain of one to six carbon atoms, including for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.
C2-6-alkenyl means a chain of from two to six carbon atoms containing one double bond, including for example ethenyl, 1-,2-propenyl, 2-,3-propenyl etc.
C2-6-alkynyl means a chain of from two to six carbon atoms containing one triple bond, including for example ethynyl, 1-,2-propynyl, 2-,3-propynyl etc.
C1-10-alkylene means a chain of one to ten carbon atoms, including for example ethylene, propylene, butylene etc. C1-6 alkylene is an alkylene group as defined above with up to 6 carbon atoms.
C2-10-alkenylene is a chain of two to ten carbon atoms containing one double bond, including for example ethenylene, propenylene, butenylene etc. C2-6 alkenylene is an alkenylene group as defined above containing from 2 to 6 carbon atoms.
C2-10-alkynylene is a chain of from two to ten carbon atoms containing one triple bond, including for example ethynylene, propynylene, butynylene etc. C2-6 alkynylene is an alkynylene group as defined above containing from 2 to 6 carbon atoms.
C3-7-cycloalkyl means cyclic alkyl of from three to seven carbon atoms, including cyclopropyl, cyclobutyl etc.
C3-7-cycloalkyl-C1-6-alkyl is composed of C3-7-cycloalkyl and C1-6-alkyl wherein C3-7-cycloalkyl and C1-6-alkyl is as defined above.
C1-6-alkoxy is xe2x80x94O-alkyl where alkyl is as defined above. C1-6-alkylthio is xe2x80x94S-alkyl where alkyl is as defined above.
Acyl means xe2x80x94COxe2x80x94C1-6-alkyl wherein C1-6-alkyl is as defined above.
Amino means NH2.
C1-6-alkylamino means xe2x80x94NHxe2x80x94C1-6-alkyl, and C1-6-dialkylamino means xe2x80x94Nxe2x80x94(C1-6-alkyl)2 where C1-6-alkyl is as defined above.
C1-6-alkoxycarbonylamino means C1-6-alkyl-Oxe2x80x94COxe2x80x94NHxe2x80x94 wherein C1-6-alkyl is as defined above.
C1-6-alkylaminocarbonylamino means C1-6-alkyl-NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein C1-6-alkyl is as defined above.
C1-6-dialkylaminocarbonylamino means (C1-6-alkyl)2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein C1-6-alkyl is as defined above.
As used herein a phenyl group which may be substituted means a phenyl group which may be substituted one or more times with a substituent selected form halogen, trifluoromethyl, cyano, nitro, amino, C1-6-alkylamino, C1-6-dialkylamino, C1-6-alkyl, C1-6-alkoxy and hydroxy.
Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Further, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (i.e. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of d- or l-(tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
The compounds of the invention can be prepared by one of the following methods comprising:
a) reducing the carbonyl groups of a compound of formula 
xe2x80x83wherein A, R1-R3, X, Y, Z, W, and the dotted line are as defined above;
b) alkylating an amine of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W, and the dotted line are as defined above with a reagent of formula Lxe2x80x94Bxe2x80x94A wherein A and B are as defined above and L is a suitable leaving group such as halogen, mesylate, or tosylate;
c) reductive alkylation of an amine of formula 
xe2x80x83wherein R1-R3, X, Y, Z, W, and the dotted line are as defined above with a reagent of formula Kxe2x80x94Bxe2x80x2xe2x80x94A, wherein A is as defined above, K is either an aldehyde or a carboxylic acid group and Bxe2x80x2 is such a group, that xe2x80x94CH2xe2x80x94Bxe2x80x2xe2x80x94 belongs to the groups defined above by B;
d) reducing the double bond of Axe2x80x2 of compounds of formula 
xe2x80x83wherein R1xe2x80x94R3, B, X, Y, Z, W, and the dotted line are as defined above and Axe2x80x2 is a group of formula Ia or Ib as defined above in which the dotted line represents a bond, in order to obtain the corresponding 2,3-dihydro derivatives, e.g. 2,3-dihydroindole or 2,3-dihydrobenzofuran;
e) reducing the double bond of the tetrahydropyridines of formula 
xe2x80x83wherein R1-R3, A, B, X, Y, and Z are as previously defined, in order to obtain the corresponding piperidine derivatives;
f) treating a compound of general formula (I) wherein Y is xe2x80x94CR6xe2x95x90CR7xe2x80x94, or wherein X and Y together form a group xe2x80x94CR4xe2x95x90CR5xe2x80x94, or xe2x80x94CR4xe2x95x90CR5xe2x80x94CR6R7 with a reducing agent in order to reduce the double bond, thereby obtaining a corresponding reduced ring system;
g) reductive removal of one or more of the substituents R1-R3 or R12-R17 in a compound of general formula (I) in which one or more of these substituents are selected from chloro, bromo, or iodo;
h) dialkylating an amine of formula 
xe2x80x83wherein R1-R3, X, Y, and Z is as defined above with a reagent of formula 
xe2x80x83wherein A and B are as defined above and L is a suitable leaving group such as halogen, mesylate, or tosylate;
i) dialkylating an amine of formula
Axe2x80x94Bxe2x80x94NH2xe2x80x83xe2x80x83(XI)
wherein A is as defined above with a reagent of formula 
wherein R1-R3, X, Y, and Z are as defined above, Wxe2x80x2 is N or CH, and L is a suitable leaving group such as halogen, mesylate, or tosylate;
j) alkylating or acylating the nitrogen atom of the group Axe2x80x3 in formula XIII, 
xe2x80x83wherein R1-R3, B, X, Y, Z, W, and the dotted line are as defined above, and Axe2x80x3 is a group selected from a group of formula Ia or Ib as defined above in which either E1, E2, or E3 is NH with alkylating or acylating reagents of formula R0xe2x80x94L, wherein L is suitable a leaving group such as halogen, mesylate, or tosylate and R0 is as defined above for R11 but not hydrogen;
k) cyclization of compounds of formula XIV, 
xe2x80x83wherein R1-R3, A, B, W, and the dotted line are as defined above and Xxe2x80x2 is selected from O or S, with dialkylatng reagents of formula Lxe2x80x94Yxe2x80x94L, wherein Y is as defined above and L is a suitable leaving group as described above;
l) cyclization of a compound of formula XVa or XVb, 
xe2x80x83wherein R1-R3, A, B, X, Y, Z, W, and the dotted line are as defined above, and L is a suitable leaving groups as defined above or is an N-imidazolyl or pentafluorophenoxy group in order to obtain the corresponding cyclic oxo-derivatives;
m) cyclocondensation of compounds of formula XVIa or XVIb, 
xe2x80x83wherein R1-R3, R6, A, B, X, Y, Z, W, and the dotted line are as defined above in order to obtain the corresponding cyclic hydroxy derivatives, or by successive dehydration to obtain the corresponding unsaturated ring system;
n) substitution of the hydroxyl group in compounds of formula XVII, 
xe2x80x83wherein R1-R3, R6-R8, A, B, X, Z, W, and the dotted line are as defined above, with cyanating reagents in order to obtain the corresponding cyano derivatives;
o) hydrolysis or reduction of the cyano group of compounds of formula XVIII, 
xe2x80x83wherein R1-R3, R6-R8, A, B, X, Z, W, and the dotted line are as defined above, in order to obtain the corresponding carboxylic acid derivatives or the corresponding aminoethyl derivatives;
p) Oxidation of the hydroxy alkyl chain in compounds of formula XIX, 
xe2x80x83wherein R1-R3, R6-R8, A, B, X, Z, W, and the dotted line are as defined above, and m=0-4, in order to obtain the corresponding carboxylic acid derivatives;
q) hydrolysis and/or reduction of the carboxylic function of compounds of formula XX, 
xe2x80x83wherein R1-R3, R6-R8, R18, A, B, X, Z, W, and the dotted line are as defined above, and m=0-4, in order to get the corresponding carboxylic acids or alcohols, respectively;
whereupon the compounds of formula (I) are isolated as the free base or in the form of a pharmaceutically acceptable salt thereof.
The reduction according to method a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminium hydride at reflux temperature. Starting compounds of formula (V), in which A is 3-indolyls, are generally prepared from reagents of formula (VI), 1,3-unsubstituted indoles, and oxalyl chloride according to known literature procedures.
The alkylation according to method b) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature. Arylpiperazine derivatives of formula (VI) are conveniently prepared from the corresponding arylamine according to the method described by Martin et al, J. Med. Chem., 1989, 32, 1052, or the method described by Kruse et al, Rec. Trav. Chim. Pays-Bas, 1988, 107, 303. The starting arylamines are either commercially available or are well described in the literature.
Aryltetrahydropyridine derivatives of formula (VI) are known from literature, cf. U.S. Pat. No. 2,891,066; McElvain et al, J. Amer. Chem. Soc. 1959, 72, 3134. Conveniently, the corresponding arylbromide is lithiated with BuLi followed by addition of 1-benzyl-4-piperidone. Subsequent treatment with acid gives the N-benzyl-aryltetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to give the corresponding ethyl carbamate followed by acidic or alkaline hydrolysis. The starting arylbromides are either commercially available or well described in the literature.
Reagents of formula Lxe2x80x94Bxe2x80x94A are either commercially available or can be prepared by literature methods, e.g. from the corresponding carboxylic acid derivative by reduction to the hydroxy derivatives and conversion of the hydroxy group to the group L by conventional methods.
The reductive alkylation according to method c) is performed by standard literature methods. The reaction can be performed in two steps, i.e. coupling of (VI) and the reagent of formula Lxe2x80x94Bxe2x80x94A by standard methods via the carboxylic acid chloride or by use of coupling reagents such as e.g. dicyclohexylcarbodiimide followed by reduction of the resulting amide with lithium aluminium hydride. The reaction can also be performed by a standard one-pot procedure. Carboxylic acids or aldehydes of formula Kxe2x80x94Bxe2x80x2xe2x80x94A are either commercially available or described in the literature.
Reduction of the double bonds according to method d) is conveniently performed by treatment with diborane or a diborane precursor such as the trimethylamine or dimethylsulfide complex in an inert solvent such as e.g. tetrahydrofuran or dioxane from 0xc2x0 C. to reflux temperature followed by acid catalyzed hydrolysis of the intermediate borane derivative. The reduction can alternatively be performed by treatment with sodium cyanoborohydride in trifluoroacetic acid, by use of magnesium metal, or by catalytic hydrogenation.
Reduction of the double bonds according to methods e) and f) is most conveniently performed by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as e.g. platinum or palladium.
The removal of halogen substituents according to method g) is conveniently performed by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at elevated temperatures in the presence of a palladium catalyst.
The dialkylation of amines according to methods h) and i) is most conveniently performed at elevated temperatures in an inert solvent such as e.g. chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide, or acetonitrile. The reaction might be performed in the presence of base such as e.g. potassium carbonate or triethylamine. Starting materials for processes h) and i) are commercially available or can be prepared from commercially available materials using conventional methods.
The N-alkylation according to method j) is performed in an inert solvent. e.g. an alcohol or ketone, at elevated temperatures in the presence of base, e.g. potassium carbonate or triethylamine, at reflux temperature. Alternatively, a phase-transfer reagent can be used.
The addition of for example a substituted vicinal dihalo derivative according to method k) by refluxing XIV in a solvent, inert to the selected reaction conditions (e.g. ketones, benzene or alcohol), in the presence of a base, e.g. potassium carbonate, triethylamine or sodium hydroxide in the presence of a phase transfer reagent (Koo, et al., J. Am. Chem. Soc. 1955, 77,5373-5375, Stillings, et al., J. Med. Chem. 1985, 28,1054-1062, Dzvinchuk, et al., Tetrahedron 1986, 386-389).
Cyclization of keto compounds according to methods l) or m) is performed, by either base treatment or by employing acidic conditions (See references above in method k, or Thixc3xa9ry, et al, Tetrahedron 1997, 53 (6), 2061-2974).
Substitution according to method n) can be performed using a Lewis acid. e.g., borontrifluoride etherate or trimethylsilyl trifluoromethanesulphonate and an activated nucleophile (trimethylsilylated compounds). (Stillings, et al., J. Med. Chem. 1985, 28,1054-1062, Thixc3xa9ry, et al., Tetrahedron 1997, 53 (6), 2061-2974).
Reactions according to method o) is performed by use of standard conditions for nitrile hydrolysis and reductions according to method o) is conveniently performed in an inert solvent such as e.g., diethyl ether or tetrahydrofuran using lithium aluminium hydride or alane.
Oxidation according to method p) can be performed by using potassium pergamanate in a sodium carbonate solution (A. Salimbeni and E. Manghisi. J. Heterocyclic Chem. 1980, 17:489-492).
Reduction according to method q) can be performed using lithium aluminium hydride in anhydrous diethyl ether or tetrahydrofuran (Koo, et al., J. Am. Chem. Soc. 1955, 77:5373-5375).
The following examples will illustrate the invention further. They are, however, not to be construed as limiting.